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1.
Steffen Vojacek Lukas Schulig Nathalie Wössner Norman Geist Prof. Dr. Walter Langel Prof. Dr. Manfred Jung Prof. Dr. Dennis Schade Prof. Dr. Andreas Link 《ChemMedChem》2019,14(8):853-864
Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling. 相似文献
2.
Yachao Dong Christos T. Maravelias Norman F. Jerome 《Optimization and Engineering》2018,19(4):937-976
We study a maritime inventory routing problem, in which shipments between production and consumption nodes are carried out by a fleet of vessels. The vessels have specific capacities and can be chartered under different agreements. The inventory levels of all consumption nodes and some production nodes should be maintained within specified bounds; for the remaining production nodes, orders should be picked up within pre-defined time windows. We propose a discrete-time mixed-integer programming model. In the face of new information and uncertainty, this optimization model has to be re-solved, as the horizon is rolled forward. We discuss how to account for different sources of uncertainty. We present a rolling-horizon reoptimization framework that allows us to study different policies that impact the quality of the implemented solution, so we can identify the optimal set of policies. 相似文献
3.
Neil P. Soice Adrian C. Maladono Doreen Y. Takigawa Arlan D. Norman William B. Krantz Alan R. Greenberg 《应用聚合物科学杂志》2003,90(5):1173-1184
Selected aromatic amides were used to model the chemical reactivity of aromatic polyamides found in thin‐film composite reverse osmosis (RO) membranes. Chlorination and possible amide bond cleavage of aromatic amides upon exposure to aqueous chlorine, which can lead to membrane failure, were investigated. Correlations are made of the available chlorine concentration, pH, and exposure time with chemical changes in the model compounds. From the observed reactivity trends, insights are obtained into the mechanism of RO membrane performance loss upon chlorine exposure. Two chemical pathways for degradation are shown, one at constant pH and another that is pH‐history dependent. An alternative strategy is presented for the design of chlorine‐resistant RO membranes, and an initial performance study of RO membranes incorporating this strategy is reported. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 1173–1184, 2003 相似文献
4.
5.
Penedo Frank J.; Dahn Jason R.; Gonzalez Jeffrey S.; Molton Ivan; Carver Charles S.; Antoni Michael H.; Roos Bernard A.; Schneiderman Neil 《Canadian Metallurgical Quarterly》2003,22(2):220
This study evaluated relations among optimism, perceived stress management skills (PSMS), and positive mood in 46 men who had surgical treatment for localized prostate cancer. The authors found that optimism, PSMS, and positive mood scores were positively correlated. Positive mood was unrelated to demographic and disease-related control variables. In a hierarchical regression model controlling for PSMS, the relationship between optimism and positive mood became nonsignificant, whereas PSMS remained a correlate of positive mood. Results suggest that the relationship between optimism and positive mood may be mediated by belief in being able to use stress management techniques effectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
6.
This paper reviews the current state of industry with regard to the introduction of software metrics. It discusses the benefits that organizations have derived from metrication, it looks at why organizations have sought to introduce metrics programmes, how they have gone about introducing those programmes and the problems that they have encountered during implementation. The review found that, on the whole, only the sanitized aspects of metrics experiences have actually been published. This seems to be especially the case with respect to practitioner resistance. Very few organizations admit to having encountered resistance during the introduction of a metrics programme. The paper also includes the results of a pilot study, conducted by the first author, which examines the attitudes that developers hold towards the introduction of software metrics. The key findings of this pilot study are that positive attitudes to metrics correlate highly with levels of education and to job satisfaction. 相似文献
7.
AM De Mattos MA Head J Everett J Hosenpud R Hershberger A Cobanoglu G Ott R Ratkovec DJ Norman 《Canadian Metallurgical Quarterly》1994,57(4):626-630
To determine if cardiac allograft outcome is improved among patients with fewer HLA-DR mismatches with their donors, we studied 132 recipients of a primary cardiac allograft who were transplanted between December 1985 and December 1991. These recipients and their donors all had high-confidence-level serological HLA-DR typing, previously shown to correlate highly with DNA DR typing. Patients were divided in two groups based on the HLA-DR mismatch with their donors. Group I consisted of 78 patients with 1 or zero DR mismatch and group II of 54 patients with 2 DR mismatches. Allograft outcome measurements included incidence of moderate rejection, incidence of allograft vasculopathy at 12 months, cardiac function measured as left ventricular ejection fraction (LVEF) and cardiac index (CI), and actuarial graft survival up to 7 years. Groups I and group II were not different with regard to recipient age, donor age, ischemia time, pulmonary vascular resistance, sex, or PRA greater than 0%. Group II had a higher incidence of moderate rejection on the first-week biopsy (47% vs. 25%, P = 0.019), and during the first month (84% vs. 58%, P = 0.006), but no difference was found in frequency of rejection from months 2 to 12. LVEF was not different in the groups at any point. CI was better in group I at 12 months (2.76 vs. 2.5, P = 0.03). No statistically significant difference was found in incidence of allograft vasculopathy (17% vs. 26%, P = 0.204). Actual graft survival at 1 year was better for group I (91% vs. 74%, P = 0.008), and actuarial graft survival at 6 years also favored group I (76% vs. 56%, P = 0.04). Using high-confidence-level serological HLA-DR typing assignments we demonstrated that HLA-DR mismatching correlates highly with cardiac allograft outcome. Implications are that heart transplant survival could be improved if prospective matching were feasible and prioritized or if immunosuppression were tailored to the HLA-DR match. 相似文献
8.
Rahul Sarpeshkar Richard F. Lyon Carver Mead 《Analog Integrated Circuits and Signal Processing》1998,16(3):245-274
Low-power wide-dynamic-range systems are extremely hard to build. The biological cochlea is one of the most awesome examples of such a system: It can sense sounds over 12 orders of magnitude in intensity, with an estimated power dissipation of only a few tens of microwatts. In this paper, we describe an analog electronic cochlea that processes sounds over 6 orders of magnitude in intensity, and that dissipates 0.5 mW. This 117-stage, 100 Hz to 10 KHz cochlea has the widest dynamic range of any artificial cochlea built to date. The wide dynamic range is attained through the use of a wide-linear-range transconductance amplifier, of a low-noise filter topology, of dynamic gain control (AGC) at each cochlear stage, and of an architecture that we refer to as overlapping cochlear cascades. The operation of the cochlea is made robust through the use of automatic offset-compensation circuitry. A BiCMOS circuit approach helps us to attain nearly scale-invariant behavior and good matching at all frequencies. The synthesis and analysis of our artificial cochlea yields insight into why the human cochlea uses an active traveling-wave mechanism to sense sounds, instead of using bandpass filters. The low power, wide dynamic range, and biological realism make our cochlea well suited as a front end for cochlear implants. 相似文献
9.
N. R. Bohidar Norman R. Bohidar Nicholas R. Bohidar 《Drug development and industrial pharmacy》1994,20(5):815-839
A discordant observation is a data point whose value is drastically different from that of the rest of the members in the data set. In the context of content uniformity experiments, however, a discordant observation arises in two ways: (i) when the value of an observation is markedly distant from that of the other data points even though it is within the required compendial range, and (ii) when the value of an observation is outside the permissible compendial range. Several statistical tests for detecting one or more discordant observations are presented. Since discordancy distorts the symmetricity of the data, several tests of symmetricity are provided. Tests for detection of group discordancy induced by discordant samples are also included. The compendial requirements are explained in statistical terms. The impact of discordant observations on compendial compliance requirements is assessed. The statistical basis of the construction of compendial limits as well as the assumptions implicit in the construction is elaborated. The results of the statistical analysis of three content uniformity studies are appropriately interpreted. 相似文献
10.
Norman F. Haard Nancy Kariel Gene Herzberg L. A. Woodrow Feltham Karl Winter 《Journal of the science of food and agriculture》1985,36(4):229-241
Fish silage was prepared from 96.5% offal obtained from Atlantic cod fillet processing and 3.5% (by wt) formic acid. The fish silage became an homogeneous liquid of low viscosity in 36–58 h at 20°C; however, the oil and protein components continued to be hydrolysed for several months. Addition of formaldehyde to fish silage (0.25 or 0.39% by wt) after liquefaction was complete, served to prevent continued protein hydrolysis and oxidative rancidity of the oil. It also decreased the development of ‘off-odours’, and the formation of total volatile bases. Fish silage was readily absorbed by hay at a ratio of 1.5 parts silage to 1.0 parts hay by weight; the product is referred to as ‘haylage’. Voluntary intake by wethers of ‘haylage’ prepared from de-oiled, formaldehyde-treated fish silage was better than for ‘haylage’ prepared from untreated fish silage. The crude protein content of ‘haylage’ rations was more than satisfactory for fattening lambs, although the energy content of ‘haylage’ rations may be a limiting factor. Retention of fish oil in the silage to increase the energy content of rations was unsuccessful because voluntary feed intake was depressed. The addition of formaldehyde to fish silage is advantageous when the product is to be fed to ruminant livestock since protein and lipid degradation in the feed, and also possibly in the rumen, are minimised and voluntary intake of ‘haylage’ by sheep is increased. 相似文献